Chronic heart failure (CHF) is one of the leading causes of death in the U.S. A primary characteristic of this disease is elevated sympatho-excitation and exercise intolerance during physical activity. During exercise in heart failure patients, extreme activation of the sympathetic nervous system is often seen and evokes an exaggerated pressor response accompanied by hyperventilation. These abnormalities potentially increase cardiovascular risk during physical activity in these patients. Experimental evidence suggests that 1) the exaggerated sympatho-excitation during exercise is directly related to an increased sensitivity of the exercise pressor reflex (EPR); and 2) the enhanced mechanically sensitive afferent component of this reflex (i.e. mechanoreflex) primarily contributes to the exaggerated EPR in CHF. The molecular and cellular mechanisms underlying the selective sensitization of the mechano-sensitive afferent limb in CHF has not fully understood. Here, we propose to test a novel hypothesis that neurotrophins (especially brain-derived neurotrophic factor, BDNF) in muscle afferent neurons play a critical role in the sensitization of the mechanical afferent limb of the EPR in CHF. We believe that this pathway operates by a mitogen-activated protein kinase (MAPK)-K+ channel mechanism. Due to underperfusion of skeletal muscle in CHF there is release of reactive oxygen species and inflammation. These stress in afferent terminal endings may stimulate muscle afferent neurons in lumbar dorsal root ganglia (DRGs) to generate neurotrophins for survival. However, effects of BDNF separate from its neurotrophic properties may also increase neuronal excitability and terminal sensitivity by activating MAPK pathways and modulating the electrical properties of voltage-gated ion channels such as K+ channels. We will use highly integrative techniques including molecular (real-time PCR, western blot, immunofluorescence and viral transfection), cellular (patch clamp) and whole animal experiments (measuring EPR function, single afferent recording) to test the BDNF hypothesis in this project. We believe that this proposed research will address important functional and mechanistic issues that directly relate to the quality of lif in patients with CHF. These data will uncover new targets for therapy in this patient population.